Respiratory failure is the major cause of mortality and long-term morbidity of very low birth weight infants. Currently, mechanical ventilation is the method of choice to treat newborns with severe respiratory failure but the risk of lung damage using such methods is high. Associated impairments may result in a life-long dependency on mechanical ventilation.
Preterm infants (22 to 36 weeks) are born during the canalicular stage of development. At this age the lungs have not fully developed and capacity for gas exchange is low. The preterm lung has a lack of surfactant causing the alveoli to collapse. Without surfactant, alveolar spaces become wet as surface tension forces increase and draw more fluid from capillaries into the alveolar airspace. As this fluid accumulates, a hyaline membrane lining accumulates consisting of fibrin, red blood cells and other cellular debris. This leads to the hyaline membrane disease or infant respiratory distress syndrome (IRDS). Pneumonia can also lead to fluid accumulation and inflammation which results in increased respiratory rate, low oxygen saturation and nausea. The hyaline membrane disease can be prevented by giving mothers who are about to deliver prematurely a group of glucocorticoid hormones such as cortisol. This will accelerate the production of surfactant. For extremely premature birth, glucorticoids are given without testing. For fetuses older than 30 weeks, their fetal lung maturity is tested by inserting a needle through the mother's uterus and obtaining the surfactant concentration in the amniotic fluid. This is used to evaluate and correlate the amount of hormone needed to be delivered.
If RDS cannot be prevented, various ways to ventilate the baby are available to allow time for the lungs to heal. Mechanical ventilation is the prime method of ventilating babies with RDS. In mechanical ventilation, an endotracheal tube is inserted into the mouth or nose and advanced to the trachea. In mechanical ventilation, breathing is provided based on a set time. In HFOV (high frequency oscillatory ventilation), high respiratory rates (>60 breaths/min) are employed in small tidal volumes. In high frequency jet ventilation (HFJV), brief “jets” of gas are exerted out of the endotracheal tube into the airway. Since the exhalation is passive, induced lung injury is reduced. Another method of ventilation is iNO (inhaled nitrogen oxide). Inability to breath properly leads to pulmonary hypertension. Nitric oxide helps regulate muscle tone in arteries and lungs. However, this can lead to haemorrhage and is toxic if used in high amounts. Although ventilation is a useful practice, it does come with its risks. Absolute pressures used to ventilate non-compliant lungs can cause lungs to collapse and become physically damaged. The pressure differences that are created between the air space and the surrounding tissue lead to barotrauma. Also, lung injury from ventilators, or infection from ventilator tubes, can lead to chronic lung disease.
Current commercial neonatal oxygenators with a hollow fiber design have priming volumes as low as 40-43 mL (Schwenkglenks et al., 2011; Tinius, Dragomer, Klutka, VanBebber, & Cerney, 2003). This is unsuitable for very low birth weight infants with a circulating blood volume of 60-100 mL/kg body weight (Nagano et al., 2005). Infants that are 500-750 g, especially with a total blood volume of 30-71 mL, would require a much lower priming volume.
Various oxygenator designs have been applied in past artificial lung experiments. Some of the earliest studies commonly used rotating-disc oxygenators for perfusion (Alexander, Britton, & Nixon, 1968; J. C. Callaghan, Angeles, Boracchia, Fisk, & Hallgren, 1963; John C Callaghan, Maynes, & HUG, 1965; Lawn & McCance, 1962). This variant of the film oxygenator served dual purposes: to facilitate blood flow through the device and to allow for gas exchange in the blood. In the 1970 s, membrane lung devices became more widely used due to its effective gas exchange properties. Zapol et al (Zapol, Kolobow, Pierce JEVUREK, & Bowman, 1969), Bui et al (Bui et al., 1992), Awad et al (Awad et al., 1995) used coiled membrane oxygenators with priming volumes of 60-70 mL and gas exchange areas between 0.4-0.8 m2. Several microporous hollow fiber oxygenators with priming volumes between 90-100 mL and gas exchange areas of 0.3-0.5 m2 were seen in the literature (Awad et al., 1995; Fujimori et al., 2001; Pak et al., 2002; Reoma et al., 2009), although non-microporous hollow fiber devices became more common within the last decade of artificial placenta study (Fujimori et al., 2001; Kuwabara et al., 1989; M Sakata, K Hisano, M Okada, & M Yasufuku, 1998; Unno et al., 1993; Masao Yasufuku, Katsuya Hisano, Masahiro Sakata, & Masayoshi Okada, 1998). Only one study among the literature used a microfluidic device in its experiments. Griffith et al (Griffith, Borovetz, Hardesty, Hung, & Bahnson, 1979) designed a microchannel oxygenator with high gas exchange properties and a priming volume of 80 mL/unit for perfusion of neonatal lambs. Thus, the filling volumes of commercial oxygenators used in animal models ranged from 60 mL to 200 mL. Due to such a large priming volume, commercial oxygenators may not be well suited for perfusion in human neonates and it would be desirable to develop an oxygenator with a lower filling volume.
Another method for dealing with respiratory failure in extremely rare cases is extracorporeal membrane oxygenation (ECMO). ECMO provides cardiac and respiratory support to patients with damaged lungs and heart. Because ECMO is a highly invasive procedure where high volumes of blood need to be pumped from a blood vessel, passed through an oxygenator and then returned to the body, it requires monitoring of many mechanical and physiological variables. Babies less than 4.5 pounds have very small vessels and high resistance. This prevents adequate flow and is not the best option for preterm infants. Also, the mechanical pump of the ECMO circuit can cause shear stress injury to blood components and lead to complications with blood clotting. Failure of the oxygenator, pump failure, tubing rupture and cannula problems, can lead to intracranial bleeding, bleeding from the surgical site, seizures and infection.
The artificial heparin-coated lung was a breakthrough in oxygenator technology. The effectiveness of a hollow fiber silicone membrane oxygenator for ECMO use was tested. This newly improved model comprised increased fiber length and surface area, increased gas transfer rate, decreased density and pressure. Heparin diluted with saline was continuously administered to all compartments of the ECMO system to prevent clotting. However, this technology only partially replaces lung functions and would not provide 100% of total body gas exchange.
In view of the risks associated with ECMO and other ventilation procedures for preterm babies, there is a need for alternate methods of treatment.